Regulation of Cholesterologenesis by the Oxysterol Receptor, LXRα

Abstract

Cholesterol is required for normal cellular and physiological function, yet dysregulation of cholesterol metabolism is associated with diseases such as atherosclerosis. Cholesterol biosynthesis is regulated by end product negative feedback inhibition where the levels of sterols and oxysterols regulate the expression of cholesterologenic enzymes. Sterol regulatory element-binding protein-2 is responsive to both sterols and oxysterols and has been shown to mediate the transcriptional response of the cholesterologenic enzymes to these lipids. Here, we show that the nuclear hormone receptor for oxysterols, the liver X receptor ␣ (LXR␣), regulates cholesterol biosynthesis by directly silencing the expression of two key cholesterologenic enzymes (lanosterol 14␣-demethylase (CYP51A1), and squalene synthase (farnesyl diphosphate farnesyl transferase 1)) via novel negative LXR DNA response elements (nLXREs) located in each of these genes. Examination of the CYP51A1 gene revealed that both the SRE and nLXRE are required for normal oxysterol-dependent repression of this gene. Thus, these data suggest that LXR␣ plays an important role in the regulation of cholesterol biosynthesis.Cholesterol is essential for maintenance of cellular membrane fluidity and is a precursor for the production of steroid hormones and bile acids. Although cholesterol is required for normal cellular and physiological function, dysregulation of cholesterol metabolism is associated with atherosclerosis and increased risk of heart disease (1). Thus, cholesterol metabolism is under strict biological regulation, and drugs inhibiting cholesterol biosynthesis such as the statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) 2 (see Fig. 1a), have been successfully utilized clinically to reduce the risk of atherosclerosis. The biosynthesis of cholesterol has long been known to be regulated by end product feedback inhibition, and this regulation has been attributed to direct regulation of the expression of several cholesterol biosynthetic genes by the sterol sensing sterol regulatory element-binding protein-2 (SREBP-2) (2). The SREBPs are responsive to both alterations in cholesterol levels as well as oxidized cholesterol metabolites known as oxysterols (3).The nuclear hormone receptors LXR␣ (NR1H3) and LXR␤ (NR1H2) have been demonstrated to be physiological receptors for oxysterols (4 -6) and regulate components of the cholesterol metabolic pathway including reverse cholesterol transport and cholesterol elimination (7). No role for the LXRs in direct regulation of cholesterol biosynthesis has been described. A recent study by Wong et al. (8) suggested that 24,25-epoxycholesterol was important for "fine-tuning" acute control of cellular cholesterol biosynthesis. Because this endogenous oxysterol is known to be one of the more potent natural oxysterol ligands for the LXRs, it is possible that some of its activity may be mediated by these receptors. Here, we show that two key cholesterologenic enzyme genes are LXR target genes and that...

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…Menaquinone is a known ligand for the nuclear receptor SXR (Tabb et al, 2003;Shearer and Newman, 2008;Zhou et al, 2009). SXR is known to heterodimerize with RXR and cross regulate LXR target genes that have wellestablished roles in modulation of cellular cholesterol efflux (Landes et al, 2003;Sonoda et al, 2005;Wang and Rader, 2007;Wang et al, , 2008bLim and Huang, 2008;Brown and Jessup, 2009;Zhou et al, 2009). Elevation of TERE1 would be predicted to increase cholesterol efflux and reduce cell cholesterol, consistent with our observations.…”

“…LXR pathways activate the apo-protein carriers such as APOAI, APOE, and the transporters such as the ATP binding cassette proteins ABC-A1, -G1, -G4, and SRBI, through which efflux proceeds to mature High density Lipoprotein, (HDL) (Tall, 2008;Zhou et al, 2010). LXR targets can be activated by oxysterols derived from the cholesterol pathway, by fatty acids, or by cross regulation from other nuclear receptors such as the steroid and xenobiotic receptor, SXR (Abildayeva et al, 2006;Tamehiro et al, 2007;Wang et al, 2008b;Zhou et al, 2009). The multiple ways these networks may be dysregulated in the context of tumor cell metabolic reprogramming are not clearly defined.…”

“…In general, the SREBP transcriptional regulator proteins activate genes for cholesterol synthesis and influx, and the Liver X Receptor, (LXR) nuclear receptors activate cholesterol efflux; however, both also regulate different aspects of fatty acid metabolism (Abildayeva et al, 2006;Wang et al, 2008b;Raychaudhuri and Prinz, 2010). LXR pathways activate the apo-protein carriers such as APOAI, APOE, and the transporters such as the ATP binding cassette proteins ABC-A1, -G1, -G4, and SRBI, through which efflux proceeds to mature High density Lipoprotein, (HDL) (Tall, 2008;Zhou et al, 2010).…”

Characterization of Cholesterol Homeostasis in Telomerase-immortalized Tangier Disease Fibroblasts Reveals Marked Phenotype Variability

“…Tangier fibroblasts thus present a cell model for oxysterol-mediated suppression of cholesterol biosynthesis. In this context, it is interesting to note that Wang and colleagues (43) have recently shown that 24-, 25-, and 27-hydroxycholesterol can suppress cholesterol biosynthesis by directly silencing the expression of two cholesterologenic enzymes (lanosterol 14a-demethylase (CYP51A1) and squalene synthase (farnesyl diphosphate farnesyl transferase 1)) via binding to novel negative LXR DNA response elements. Altogether, these studies suggest a dual regulation of cholesterol biosynthesis via SREBP2 and LXR.…”

Liver X receptor modulators: Effects on lipid metabolism and potential use in the treatment of atherosclerosis

“…Smaller increases in the hepatic expression of these genes, except SREBP-2, were also observed in LXRβ-deficient mice [22]. However, very recent data suggest that LXRα can act as an inhibitor of cholesterol biosynthesis by directly silencing the expression of two cholesterogenic enzymes, the lanosterol 14α-demethylase (CYP51A1), and squalene synthase [23]. Finally, whereas no differences were seen in the regulation of LDLR gene expression in LXRα-deficient mice under basal conditions [21], LXRα activation has been reported to induce expression of the LDLR gene in hepatoblastoma cells, in a SREBP-independent manner [24].…”